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Methotrexate-Related Pulmonary Complications in Rheumatoid Arthritis

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Methotrexate-Related Pulmonary Complications in Rheumatoid Arthritis 434 Annals of the Rheumatic Diseases 1994; 53: 434-439 REVIEW Ann Rheum Dis: first published as 10.1136/ard.53.7.434 on 1 July 1994. Downloaded from Methotrexate-related pulmonary complications in rheumatoid arthritis Pilar Barrera, Roland F J M Laan, Piet L C M van Riel, P N Richard Dekhuijzen, Agnes M Th Boerbooms, Levinus B A van de Putte Methotrexate (MTX) was described as a drug cosis,2627 aspergillosis,28 29 disseminated histo- in 1946' and first used in the treatment of plasmosis,28 parainfluenza virus infection'2 and human disease (childhood leukaemia) in cytomegalovirus pneumonia.30 Pulmonary 1948.2 Successful MTX treatment for candidiasis was described in one patient with rheumatoid arthritis (RA) and psoriasis was polymyositis/dermatomyositis treated with reported in 1951,3 although the interest in this MTX3' but, to our knowledge, not in RA. drug at that time was probably overshadowed Although some of the reported infections by the impressive results of cortico-steroid appeared during concomitant treatment with treatment until approximately 1980. MTX was corticosteroids, these studies suggest a approved by the food and drug administration potential immunosuppressive effect of low- (FDA) for the treatment of severe and dis- dose MTX treatment at least in some patients. abling psoriasis in 1971 and for RA only in The present review will focus on MTX- 1988.4 pneumonitis. MTX-related pulmonary toxicity was first observed during treatment of childhood leukaemia in 19695 and later in malig- Pathogenesis nancies, psoriasis6 7 and polymyositis.7 I The mechanism of MTX-induced lung Though it was postulated that pulmonary pathology remains unclear. Lung damage due toxicity would appear only with a weekly dose to folate deficiency has been suggested32 but higher than 20 mg,7 this did not prove to be seems unlikely since MTX pneumonitis may true when in 1983 pneumonitis was also occur after a single MTX dose33" and is not reported during low-dose MTX treatment for prevented by folinic acid treatment.35 A hyper- RA9 10 sensitivity reaction is suggested by findings in http://ard.bmj.com/ lung biopsies: interstitial pneumonitis, granuloma formation and bronchiolitis,7 and in Infectious and non infectious pulmonary brochoalveolar lavage: lymphocytic alveolitis, complications increased eosinophils and reversed CD4/CD8 In recent years there has been an increase in ratio,3637 together with the clinical findings of the number of reports of pulmonary fever, peripheral eosinophilia and response to complications associated with low-dose corticosteroids. The reports of spontaneous on September 30, 2021 by guest. Protected copyright. methotrexate therapy for rheumatic and non- remission during MTX treatment7 and rheumatic diseases including both non rechallenge of the drug without recurrence of infectious and infectious pathology. Among lung pathology'3 argue more for an the non infectious complications observed in idiosyncratic reaction than for hypersensitivity. patients with RA, interstitial pneumonitis has A specific cellular immune reaction to the drug been most often reported7 9-13 (more than 35 has been suggested by the production of a cases since the first reports in 1983).9 "0 lymphokine which inhibits leukocyte migration Interstitial lung fibrosis has been observed [leukocyte inhibitor factor (LIF)] by peripheral during MTX treatment for RA, malignancies blood lymphocytes after incubation with and psoriasis.6 1' Furthermore, one case of MTX. LIF production was observed in accelerated pulmonary nodulosis'4 and one of patients with MTX pneumonitis but not in drug-induced asthma'5 have so far been other patients treated with MTX or healthy Departments of Rheumatology and described during MTX treatment for RA. controls.38 39A toxic drug reaction is suggested Pulmonology*, Lung fibrosis and nodulosis may be pulmonary by the accumulation of MTX in lung tissue,40 University Hospital manifestations of RA,16 and it is therefore the biopsy findings of alveolar and non-specific Nijmegen, The to and the resolution of Netherlands difficult to ascribe this pathology only MTX lung injury,6 pathology P Barrera treatment. Two other complications, so far after stopping or lowering the drug.4' The fact RFJMLaan only observed during treatment with MTX in that pulmonary pathology does not appear to P LC M van Riel are oedema'7'18 be related to cumulative MTX dose argues, P N R Dekhuijen* malignant diseases, pulmonary A M Th Boerbooms and isolated pleuritis.'9 against this hypothesis. L B A van de Putte Among the pulmonary infections during Correspondence to: MTX treatment of RA, the most frequently Dr Pilar Barrera, Department of reported has been Pneumocystis cannii pneu- Risk factors Rheumatology, University monia with more than eight cases published Age, sex, and disease duration are not Hospital Nijmegen, PO Box of MTX- 9101, 6500HB Nijmegen, since 1983.2"25 Less frequently observed associated with the development The Netherlands. infections include pulmonary cryptococ- pneumonitis. This complication has been Methotrexate-related pulmonaty complications in rheumatoid arthritis 435 observed after oral,4' intravenous,42 intra- character of the diagnosis. The incidence of muscular,41 intrathecal43 and even local34 abnormalities in clinical, laboratory and administration of MTX. No correlation has radiological examination in patients with Ann Rheum Dis: first published as 10.1136/ard.53.7.434 on 1 July 1994. Downloaded from been found between the occurrence of lung MTX-pneumonitis is difficult to estimate since toxicity and cumulative or weekly dose or this complication is relatively uncommon and dosage schedule.'3 Pneumonitis has been large patient series are lacking. Data presented observed after as little as 12X5 mg MTX33 34 in the following sections were deducted from and may appear even weeks after dis- previous studies. continuation of treatment.446 In view of the relative rarity of MTX pneumonitis in other non-malignant diseases like psoriasis47 and Clinical features and physical bronchial asthma,48 a propensity to pulmonary examination involvement in RA has been suggested33 but so The most usual complaints include dyspnoea far comparative studies on the incidence of and fever.9-l3 Non productive cough has been MTX-pneumonitis in RA and other diseases reported in 75% of the patients.54 Pleuritic are lacking. A possible relationship between chest pain may also be present but is rare.3 19 certain HLA haplotypes and increased risk for In most patients a subacute clinical course is MTX-pneumonitis has been mentioned in two observed during some weeks, but acute previous reports: DRw3 in one case33 and presentations have been also described.33 On A2,24;DR4 in two cases.49 We also observed examination, tachypnoea (in 38-52% of the the HIA DR4 haplotype in four offive patients patients), crepitant rales (in 31-45% of the with MTX-related lung toxicity admitted to patients) and cyanosis (in 52% of the patients) our unit during 1993, but studies in larger are common findings.7 913 5 Abnormalities on patient groups are needed. auscultation may be disproportionately scarce Renal function impairment'3 50 and con- compared with the extensive radiological comitant use of non steroidal anti-inflam- findings.33 matory drugs'2 have been suggested to predispose to MTX-toxicity in some studies but this has not been confirmed by others.5' Laboratory investigations Specific risk factors for the development of As for the clinical findings and physical MTX pneumonitis are not known exactly but examination, no specific results of laboratory some studies have suggested that a history tests are diagnostic for MTX-pneumonitis. of smoking,'2 pre-existing pulmonary Hypoxaemia is observed in 90-95% of the disease2 52 53 and abnormal chest radiographs cases.7 9-13 54 The white blood cell count may before MTX institution53 might be predis- be normal7 or show moderate leukocytosis posing factors. without left shift.9 13 Mild eosinophilia has been reported in 41% of the patients7 54 and http://ard.bmj.com/ elevated levels of lactate dehydrogenase Diagnosis (LDH)'0 13 have been reported. The diagnosis of MTX-pneumonitis is difficult Investigations directed to exclude infectious since there are no pathognomonic findings and pathology should consist of extensive cultures this condition may mimic other pulmonary of sputum, blood and bronchoalveolar lavage diseases. When a patient treated with MTX (BAL) fluid and serological test for common develops new respiratory symptoms, the respiratory viruses, mycoplasma, rickettsia and on September 30, 2021 by guest. Protected copyright. differential diagnosis includes MTX- legionella. Microscopical examination of BAL pneumonitis, rheumatoid lung disease, and fluid is recommended to exclude Pneumocystis pulmonary infection or emboli. Exclusion of carinii, fungi and mycobacteria. BAL cell other pathology, particularly of infectious analysis usually reveals* hypercellularity and origin, is time consuming and therefore MTX- lymphocytosis.3637 Mild eosinophilia36 or pneumonitis is often diagnosed retrospectively. neutrophilia37 and increased percentages of Criteria, proposed by two different groups,'2 13 either CD436 or CD8 lymphocytes37 38 have (table 1) are helpful for diagnostic purposes, also been reported. The diagnostic value of but the term 'definite' MTX-pneumonitis'2 BAL cell analysis is limited since lympho- should be avoided in view of the presumptive cytosis, increases in CD4 and decreases in Table 1 Diagnostic criteria ofMTX-pneumonitis
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